Physiology

Nope, it doesn’t! As long as their vacation is just for a week or two, they would totally feel like this LA weather, even at night, is pretty warm!

When your body temperature is dropping because it’s been consistently cold over several days or weeks, your body ramps up production of your thyroid hormone. Your thyroid hormone is what regulates your metabolism. And your metabolism is only about 40% efficient, meaning that when sugars/fats/proteins are converted to usable energy (ATP), about 40% of the original molecules are used as ATP, and 60% is given off as heat. This is why your body is 98.6°F (37°C), meaning all these metabolic processes are giving off lots of heat! Your car engine, is about 20% efficient. About 80% of the gasoline being burned is wasted in the form of heat, hence why that engine oil and exhaust is scalding hot!

So anyway, when the temperatures get colder… the thyroid hormone production increases, causing your metabolism to increase, CAUSING YOUR BODY TO GENERATE MORE HEAT. This then causes you to feel HUNGRY because food is the fuel to supplement this energy production. This is why places like Minnesota are called “Meat and Potatoes Country.” During the winter months, you may have an insatiable appetite due to this ramped up basal metabolism. It doesn’t help that we have all these holiday dinners (thanksgiving/christmas) placed at the perfect time. And of course since we wear long sleeves and big coats which helps to hide the fat, we gain weight without even realizing it.

Now, when the temperatures start warming up and your body isn’t struggling to always stay warm, thyroid production will decrease. When temperatures get downright hot and humid, thyroid production will decrease even further, to slow down metabolism. This is why in the heat, people don’t have a big appetite. Instead of having giant meals like they would’ve in the winter, they rather have light salads in the summer time.

So when a person is visiting LA from Minnesota, their base metabolic rate is very high compared to ours. When they come here and it’s 55°F out, they can stay out here in shirts and shorts and feel fine. Eventually though, their bodies will acclimate of course. Hope that helps. 🙂

Glycine and GABA: Glycine is one of the 20 amino acids. Some neurons absorb this and it slows down electrical activity in the nervous system. Another one is gamma-aminobutyric acid (GABA). But the two we really want to focus on are serotonin and endorphins.

Serotonin is actually made from the amino acid tryptophan. While most amino acids have the ending of -ine, tryptophan doesn’t. It’s converted by some of our neurons to become 5-hydroxy tryptamine (serotonin). So serotonin is chemically known as 5-OH Tryptamine made from the amino acid tryptophan. Serotonin is very important for putting someone to sleep. It is important in natural/sleep wake patterns. This raises a whole new issue, since we know amino acids are acting like neurotransmitters. If we eat food that contains amino acids, does that affect human behavior? The effects are subtle. The effects are not as strong like it is with drugs. There’s a lot of tryptophan in turkey which is converted by the neurons into serotonin. But is that why they get sleepy after thanksgiving?

First off, people eat 3-4 times the normal volume of food during Thanksgiving. Secondly, they’re eating foods very high in carbs (yams, stuffing, bread). All these things make us very sleepy. Milk is also high in tryptophan (proverbial warm cup of milk). There are also cheeses high in the amino acid tyrosine that convert into the catecholamine’s. So it’s probably not the tryptophan in turkey, but the whole combination.

Endorphins is a contraction of the word endogenous morphine meaning we have a neurotransmitter that comes from us that works like morphine. The next time you take heroin, it mimics the action of the endorphin neurotransmitter. So when do endorphins get released? Orgasms. Orgasms are the next best thing to taking heroin. But that lasts only for some minutes or an hour. If you want to feel relaxed and sleepy for hours, then take heroin. There’s also something called a runners high that’s associated with an extended exercise session and the postulation is that is from the endorphin release. Narcotics stimulate those endorphin receptor sites for hours instead of minutes.

Why do we need these inhibitory neurotransmitters?

By having both inhibitory and excitatory, we could weigh different factors and make decisions. So it helps with decision making. When you go to sleep do your ears stop working? No. If it stopped working, your alarm wouldn’t work. Your ears are working 24/7, so how come you’re not hearing anything when you’re asleep? Because your brain is ignoring everything and that’s due to these inhibitory neurotransmitters which allow us to ignore stimuli or input signals. We will eventually talk about the role of neurotransmitters in terms of ADD, because that’s when somebody doesn’t have enough of the inhibitory neurotransmitters.

The excitatory NT’s create a local depolarization (EPSP) and they activate it by opening ligand gated sodium ion channels. In the nervous system, however, there are other neurons that are inhibitory NT’s (IPSP) and when they activate a receptor site, instead of opening up a ligand gated sodium ion channel, it opens either a potassium ion channel or calcium ion channel and the inside of the cell becomes more negative (hyperpolarization).

We just went over ACh, glutamic acid and the catecholamines.

These catecholamines are all derived from the same amino acid tyrosine. When the catecholamine NT’s activate the receptor site, they don’t directly cause an opening of ligand-gated ion channels. They actually trigger adenylyl cyclase which converts ATP to cyclic AMP which increases the permeability of the ligand-gated sodium ion channels which leads to increased electrical activity in the cell. Cyclic AMP acts as a second messenger (intracellular messenger) and of course there must be an enzyme that breaks down this AMP otherwise it would continue to activate whatever it is doing for the rest of your life.

MAO breaks down the catecholamine neurotransmitters, however, since it’s the c-AMP that opens up the sodium ion channels, there is an enzyme called phosphodiesterase which breaks down the cyclic-AMP.

In summarizing, there are 3 different ways of mimicking the action of catecholamines:

One is to give a mimetic (amphetamine and ephedrine),

A second way is to use a drug called a MAO inhibitor which would prevent the catecholamines from breaking down and their effects would be prolonged or exaggerated.

The third thing you could do is to give a drug called a phosphodiesterase inhibitor, such as caffeine, which prevents the cyclic-AMP from being broken down. These all have excitatory effects.

Nitric Oxide, a gas released from the synaptic knobs of some neurons causes blood vessels to dilate.

It’s obvious why we have excitatory NT’s, if we didn’t, nothing would happen. So why do we need inhibitory ones?

The first one is sleeping. We need inhibitory NT’s to ignore sensory input. When you go to sleep do your ears stop working and the answer is no, all your sensory neurons are continuously sending info to your brain and the only way you could go into this sleep state is to ignore all this information through the release of inhibitory neurotransmitters. It appears all vertebrate animals need sleep. The higher the level the more sleep they get. Which would make cats the most intelligence because they sleep 30 hours in 24 hours in a day.

Second role of inhibitory NT’s: it permits sensory discrimination and attention. Sensory overload leads to seizures. Epilepsy is due to over-excitation/stimulation of the brain. So if we don’t have inhibitory NT’s we go into seizures. This also comes up in the subject of ADD. So in ADD, a child or adult has trouble focusing on what’s important because they easily get distracted by other stimuli. They have no way of inhibiting the sensory input signals. They commonly could take medication and curiously they are stimulants. The stimulant drugs in your brain stimulate your brain to release inhibitory neurotransmitters.

A third reason why we have inhibitory NT’s is to give us fine motor control. In order for somebody to be a surgeon, dancer, musician, anything that involves precision, we not only activate somatic motor neurons, but simultaneously inhibit motor neurons to OTHER skeletal muscles. If somebody doesn’t have these inhibitory motor neurons their movements will be gross and exaggerated. An over stimulation of somatic motorneurons leads to convulsions. This is an over-excitation of skeletal muscles and is associated with epilepsy again.

We must clarify that there is a difference between convulsions and epilepsy.

A seizure is too much input signal (no way of ignoring what’s coming in).

A convulsion is too much motor output (too much excitation occurring going to the skeletal muscles).

All epilepsy is associated with seizures but not all epilepsy is associated with convulsions.

As the brain develops as you go from an infant to a child to an adolescent to an adult, the brain develops and one of the things it’s developing is the release of inhibitory NT, so concentration and attention improves as we grow older. It’s not very important for a 3 year old to stay focused. Developmentally, movements of a child exhibit gross motor movements. As we grow we develop better fine motor movements. This kind of explains why ADD is developmentally related.

Another clinical considerations: Tetanus

Tetanus is caused by a bacterial infections (c. tetani; gram negative; produces exotoxins). These exotoxins interfere with inhibitory neurotransmitters and the result is seizures and convulsions. The reason tetanus is called “lock jaw” is because the muscles of the face are the ones that constrict first and when someone dies from it, it looks like a convulsion.

There’s literally hundreds of neurotransmitters they’ve discovered and we’re only going to mention a few of them here. The following are usually excitatory (usually, meaning, there are exceptions!):

Acetylcholine (ACh) certainly excites the nervous system. If you inject someone with ACh, when it reaches their brain it will open up sodium ion channels and depolarize them but it wont last long because there’s acetylcholinesterase. That’s why they would use a mimetic (a synthetic drug that’s similar but slightly different than our normal neurotransmitter that would take hours for our enzyme to break down rather than minutes).

Glutamic acid: A large number of neurotransmitters are amino acids or modified amino acids. Certainly in a biology class, we have learned that amino acids are the building blocks for making proteins, but now I’m telling you another role of amino acids. Many neurons either simply release amino acids as neurotransmitters or the neurotransmitter is a modified amino acid. Glutamic acid is a name of one of the amino acids. It excites and increase electrical activity but its effects don’t last long because there’s enzymes that break it down.

Nitric Oxide: They discovered this 30 years ago and they couldn’t believe it at the time. Nitric oxide is a gas released by some neurons from their synaptic knobs which goes into blood vessels and the main action is vasodilation.

First off, if you want to know about nitric oxide sooner rather than later, look up Viagra. Viagra dilates the blood vessels in the penis and it does that by triggering the release of NO in the vessels of the penis.

Some of you have heard that when somebody needs their coronary arteries to be dilated (like people with angina pectoris), they give a coronary vasodilator called nitroglycerine which mimics the action of nitric oxide. Nitroglycerine, in other words, is a mimetic or agonist.

Catecholamines

norepinephrine (noradrenalin)

epinephrine (adrenalin)

dopamine

The three neurotransmitters above are made from the amino acid tyrosine and are collectively called catecholamines. Tyrosine is one of the essential amino acids and it absorbs something called L-DOPA (dihydroxy-phenylalanine) and some of the enzymes convert it into dopamine.

Other neurons turn the dopamine enzymatically into norepinephrine (which has a OH group).

Other neurons, after they form norepinephrine, convert it one more step into epinephrine (which has a CH3 group).

If you inject someone with epinephrine, it’s going to increase their electrical activity in their body and last for 5 minutes because the enzymes break it down really quickly. The enzyme that breaks down all three catecholamine’s is called Monoamine Oxidase (MAO). Just like how acetylcholinesterase breaks down acetylcholine, MAO’s break down catecholamine’s.

Why do MAO and MAO inhibitors work with catecholamines?

At the end of dopamine is NH2. That’s an amine. The end of norepinephrine and epinephrine have NH2 as well. So they all have one amine group (monoamine) and monoamine oxidase can break that off.

If you want the effects of epinephrine going on, you have to give an IV drip, but one of the things you could do to make the epinephrine last longer is stop the enzyme from working. This is how monoamine oxidase inhibitors (MAOI) work, which are commonly anti-depressants, although they are not prescribed as often now.

The chemical structures of amphetamine and epinephrine look very alike. Structurally they are very similar. The main difference between epinephrine and amphetamine are the missing OH’s. Due to this, amphetamine will activate the same receptor sites as norepinephrine but not break down as quickly.

There’s a little more to the story for catecholamine’s.

When we went over proteins in the cell membrane, we went over a diagram. When a ligand attaches to a receptor site, it activates a g-protein and normally most neurotransmitters (ligands) cause an ion channel to open. We gave the example of acetylcholine activating the receptor site causing the sodium channels to open (exactly what happens at the neuromuscular junction). Epinephrine does not directly open up an ion channel. It activates an enzyme. So it works a little bit different than most NT’s. All catecholamine’s activate an enzyme called adenyl cyclase. (They’ve changed the spelling of the name to adenylyl cyclase).

Adenylyl cyclase converts a small number of ATP’s (adenosine TRIphosphate) into cyclic-AMP and PPi.

PPi = two phosphate groups

AMP = one phosphate group

Adenylyl cyclase converts A-P-P-P(ATP) into A-P (AMP) because cyclase enzyme breaks it off before the second phosphate. Now what the hell is AMP? AMP is commonly called the intracellular messenger (the second messenger) and it causes the opening up of sodium ion channels. In other words, cyclic AMP is what increases the permeability of the sodium ion channels.

Aren’t I still saying that the catecholamine’s open up the sodium ion channels? Yes, but we’ve added an intermediate step for catecholamine’s that c-AMP has to be formed that is actually what is opening up the sodium ion channels.

Just like how there is an enzyme for everything, you have to break down c-AMP because it’s what’s actually making the sodium channel open. The enzyme that breaks down c-AMP is phosphodiesterase is what breaks down c-AMP into the “metabolite” 5’AMP. The metabolite is the inactivated form.

So, the catecholamines activate adenylyl cyclase enzyme that creates c-AMP. And phosphodiestease is what breaks down c-AMP to be inactive.

What if we had a drug that inhibited phosphodiesterase?

That means c-AMP won’t be broken down and it will accumulate. Cyclic AMP excites our neurons because of the indirectly-adrenalin-made c-AMP. The phosphodiesterase inhibitor that all of us have tried is caffeine.

So you could take a mimetic like methamphetamine or take a MAOI or a phosphodiesterase inhibitor and they would all do the same thing.

People talk about herbal and regular tea. Herbal teas are like chamomile, mint, etc and they don’t have caffeine in them. Real tea has “caffeine” in it but it’s actually not caffeine but it’s similar to it. Theophylline is the caffeine-like chemical that’s in tea that’s also a phosphodiesteraste inhibitor and is used in medicine under the brand name Theodur or Monodur.

The context that they use these are for people with really bad asthma. So they won’t usually give them adrenalin but something that mimics adrenalin called albuterol (proventil) that actives these receptor sites but specifically on the airways and helps dilates airways. When it’s really bad asthma, they add theophylline (side effect is that it speeds up the heart rate) to the albuterol to really help jack up the c-AMP levels.

Now let’s go over examples of neurotransmitters that are USUALLY inhibitory…

Some neurons in the CNS release neurotransmitters that excite other neurons (meaning to fire off APs) and some inhibit (prevent) the generation of action potentials.

Action of Excitatory Neurotransmitters

Presynaptic neurons are the neurons that conduct the AP to release a neurotransmitter and they affect the postsynaptic neurons. What ALWAYS causes a neuron to release any neurotransmitter (whether it is excitatory or inhibitory) is an action potential.

Question and reminder: Where are most of the potassium ions normally found in the body?

Most are found inside the cells and of course there are negatively charged proteins inside the cell.

Where are most of the sodium ions found?

Outside the cell. There is an excess of negative charges inside and excess of positive outside and this is known as the resting state).

ALL excitatory neurotransmitters cause an opening of ligand-gated sodium ion channels. As a result, sodium ions flow in and the cell becomes less negative on the inside. When we talk about acetylcholine, it activates ACh receptor sites and ligand gated sodium ion channels open. These excitatory neurotransmitters create a local increase of permeability of sodium ion channels (ligand gated sodium channels open) which leads to a local depolarization that’s known as an Excitatory Postsynaptic Potential (EPSP) because we are exciting the post-synaptic cell. So whether the excitatory neurotransmitter is dopamine or norepinephrine or anything else, it’s going to always open up ligand-gated sodium ion channels, causing the inside to be less negative.

Action of Inhibitory Neurotransmitters

If an action potential goes down the synaptic knob of another neuron and releases an inhibitory neurotransmitter, it’s going to be activating specifically different receptor sites on the cell membrane of the postsynaptic cell.

When an inhibitory NT activates the receptor site, it causes additional potassium channels to open which may cause potassium ions to flow out of the cell and if additional positively charged potassium ions flow out of the cell, the inside of the cell will become more negative.

In other words, inhibitory neurotransmitters cause an opening of ligand-gated potassium ion channels which leads to a local hyperpolarization (more negative than normal). This is known as a Inhibitory Postsynaptic Potential (IPSP) because it’s going to be LESS likely to throw off an action potential.

Contrast that with exitatory NTs: All excitatory neurotransmitters cause an opening of ligand-gated sodium ion channels.

The inhibitory NT could also cause an opening up of ligand-gated Chloride Ion channels. Chloride is mostly outside the cell and it’s negatively charged. When these channels open, negatively charged ions will flow inside the cell, making it more negative (local hyperpolarization).

Whether potassium ions go out the cell or chloride ions go in the cell, the cell becomes hyperpolarized.

Summation of Post-Synaptic Potentials

So what’s this postsynaptic neuron going to do if both these EPSP and IPSP’s are firing off together? It depends on the sum of all these influences. Whether a neuron generates an Action Potential, or not, this depends on the overall sum of EPSP’s and IPSP’s occurring in the neuron at any moment in time.

Let’s say there’s a neuron in my brain that determines whether I buy pizza or not…

Let’s pretend it’s an interneuron (since those are involved with memory, learning, and decision making). Imagine someone walks in with fresh pizza and I go “Wow I want pizza!” It’s going to be pushing the action potential of that neuron to the edge. Then you think maybe I shouldn’t cause I just ate and I’m not even hungry! But then I smell the pizza and I really want it again. Now I’m thinking I have only $2 on me so I really shouldn’t buy the pizza. So should I? There’s factors telling me I should and shouldn’t buy the pizza.

The point is, the way our nervous system allows us to make decisions are with the summation of Excitatory Postsynaptic Potentials (EPSP) and Inhibitory Postsynaptic Potentials (IPSP). It’s like the devil and angel on the shoulders-act.

Temporal summation

Temporal summation is the summation of EPSP’s or IPSP’s due to repeated stimulation by one neuron.

Stimuli applied to the same axon sufficiently close together in time add together to depolarize the membrane.

Look at the picture on the right. The Y-axis of the graphs are Membrane Potential (mV) and it shows that the cell starts out with -70.

At the bottom graph, when one neuron repeatedly fires, affecting a pos synaptic neurons, this is summing in time (temporal summation) that causes an action potential.

What would’ve happened if neuron B released its inhibitory NT repeatedly? It would hyperpolarize more and more, making it more and more negative, making it less and less likely to fire off an AP.

Spatial Summation

There’s also something called spatial summation which is the summation of EPSP’s or IPSP’s due to stimulation by more than one neuron simultaneously.

Top graph: Let’s see what causes a local depolarization (an action potential).

Neuron #1 releases, Neurons #2 releases, Neuron #3 releases. Then Neurons 1 and 2 release. When Neurons 1+2+3 release at the same time, the sodium channels open, we go beyond the threshold potential and have an action potential.

Question: What if neuron A released its excitatory NT at the same time neuron B released its inhibitory NT?

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